title: High affinity glycosaminoglycan and autoantigen interaction explains joint specificity in a mouse model of rheumatoid arthritis.
abstract: In the K/BxN mouse model of rheumatoid arthritis, autoantibodies specific for glucose-6-phosphate isomerase (GPI) can transfer joint-specific inflammation to most strains of normal mice. Binding of GPI and autoantibody to the joint surface is a prerequisite for joint-specific inflammation. However, how GPI localizes to the joint remains unclear. We show that glycosaminoglycans (GAGs) are the high affinity (83 nm) joint receptors for GPI. The binding affinity and structural differences between mouse paw/ankle GAGs and elbows/knee GAGs correlated with the distal to proximal disease severity in these joints. We found that cartilage surface GPI binding was greatly reduced by either chondroitinase ABC or beta-glucuronidase treatment. We also identified several inhibitors that inhibit both GPI/GAG interaction and GPI enzymatic activities, which suggests that the GPI GAG-binding domain overlaps with the active site of GPI enzyme. Our studies raise the possibility that GAGs are the receptors for other autoantigens involved in joint-specific inflammatory responses.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Studelska
authors.forename: Laura
authors.initials: L
authors.lastname: Mandik-Nayak
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Pan
authors.forename: Peter
authors.initials: P
authors.lastname: Weiser
authors.forename: Lynda M
authors.initials: LM
authors.lastname: McDowell
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
authors.forename: Fei F
authors.initials: FF
authors.lastname: Shih
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001324:Autoantigens / Q000276:immunology*; D055162:Biocatalysis; D002356:Cartilage / Q000378:metabolism; D004187:Disaccharides / Q000378:metabolism; D004195:Disease Models, Animal; D005956:Glucose-6-Phosphate Isomerase / Q000378:metabolism; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D001324:Autoantigens; D004187:Disaccharides; D006025:Glycosaminoglycans; D005956:Glucose-6-Phosphate Isomerase